Prosthetic tissue valves

ABSTRACT

A prosthetic valve comprising a conical shaped ribbon structure comprising an extracellular matrix (ECM) composition. The ribbon structure comprises a plurality of elongated ribbon members that are positioned proximate each other in a joined relationship, wherein the ribbon members are positioned adjacent each other and form a plurality of fluid flow modulating regions that open when fluid flow through the valve exhibits a negative flow pressure and open when fluid flow through the valve exhibits a positive flow pressure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.15/206,833, filed on Jul. 11, 2016, now U.S. Pat. No. 10,188,510, whichis a continuation-in-part application of U.S. application Ser. No.14/960,354, filed on Dec. 5, 2015, now U.S. Pat. No. 9,907,649, which isa continuation-in-part application of U.S. application Ser. No.14/229,854, filed on Mar. 29, 2014, now U.S. Pat. No. 9,308,084, whichclaims priority to U.S. Provisional Application No. 61/819,232, filed onMay 3, 2013.

FIELD OF THE INVENTION

The present invention generally relates to prosthetic valves forreplacing defective cardiovascular valves. More particularly, thepresent invention relates to prosthetic atrioventricular valves andmethods for anchoring same to cardiovascular structures and/or tissue.

BACKGROUND OF THE INVENTION

As is well known in the art, the human heart has four valves thatcontrol blood flow circulating through the human body. Referring toFIGS. 1A and 1B, on the left side of the heart 100 is the mitral valve102, located between the left atrium 104 and the left ventricle 106, andthe aortic valve 108, located between the left ventricle 106 and theaorta 110. Both of these valves direct oxygenated blood from the lungsinto the aorta 110 for distribution through the body.

The tricuspid valve 112, located between the right atrium 114 and theright ventricle 116, and the pulmonary valve 118, located between theright ventricle 116 and the pulmonary artery 120, however, are situatedon the right side of the heart 100 and direct deoxygenated blood fromthe body to the lungs.

Referring now to FIGS. 1C and 1D, there are also generally fivepapillary muscles in the heart 100; three in the right ventricle 116 andtwo in the left ventricle 106. The anterior, posterior and septalpapillary muscles 117 a, 117 b, 117 c of the right ventricle 116 eachattach via chordae tendinae 113 a, 113 b, 113 c to the tricuspid valve112. The anterior and posterior papillary muscles 119 a, 119 b of theleft ventricle 106 attach via chordae tendinae 103 a, 103 b to themitral valve 102 (see also FIG. 1E).

Since heart valves are passive structures that simply open and close inresponse to differential pressures, the issues that can develop withvalves are typically classified into two categories: (i) stenosis, inwhich a valve does not open properly, and (ii) insufficiency (alsocalled regurgitation), in which a valve does not close properly.

Stenosis and insufficiency can occur as a result of severalabnormalities, including damage or severance of one or more chordeae orseveral disease states. Stenosis and insufficiency can also occurconcomitantly in the same valve or in different valves.

Both of the noted valve abnormalities can adversely affect organfunction and result in heart failure. By way of example, referring firstto FIG. 1E, there is shown normal blood flow (denoted “BF_(N)”)proximate the mitral valve 102 during closure. Referring now to FIG. 1F,there is shown abnormal blood flow (denoted “BF_(A)”) or regurgitationcaused by a prolapsed mitral valve 102 p. As illustrated in FIG. 1F, theregurgitated blood “BF_(A)” flows back into the left atrium, which can,if severe, result in heart failure.

In addition to stenosis and insufficiency of a heart valve, surgicalintervention may also be required for certain types of bacterial orfungal infections, wherein the valve may continue to function normally,but nevertheless harbors an overgrowth of bacteria (i.e. “vegetation”)on the valve leaflets. The vegetation can, and in many instances will,flake off (i.e. “embolize”) and lodge downstream in a vital artery.

If such vegetation is present on the valves of the left side (i.e., thesystemic circulation side) of the heart, embolization can, and oftenwill, result in sudden loss of the blood supply to the affected bodyorgan and immediate malfunction of that organ. The organ most commonlyaffected by such embolization is the brain, in which case the patientcan, and in many instances will, suffer a stroke.

Likewise, bacterial or fungal vegetation on the tricuspid valve canembolize to the lungs. The noted embolization can, and in many instanceswill, result in lung dysfunction.

Treatment of the noted heart valve dysfunctions typically comprisesreparation of the diseased heart valve with preservation of thepatient's own valve or replacement of the valve with a mechanical orbioprosthetic valve, i.e. a prosthetic valve.

Various prosthetic heart valves have thus been developed for replacementof natural diseased or defective heart valves. Illustrative are thetubular prosthetic tissue valves disclosed in Applicant's U.S. Pat. Nos.9,044,319, 8,709,076 and 8,790,397, and Co-Pending U.S. application Ser.Nos. 13/560,573, 13/804,683, 13/480,347 and 13/480,324. A furthertubular prosthetic valve is disclosed in U.S. Pat. Nos. 8,257,434 and7,998,196.

Heart valve replacement requires a great deal of skill and concentrationto achieve a secure and reliable attachment of a prosthetic valve to acardiovascular structure or tissue. Various surgical methods forimplanting a prosthetic valve have thus been developed.

The most common surgical method that is employed to implant a prostheticvalve (mitral or tricuspid) comprises suturing a circular synthetic ringof a prosthetic valve to the annular tissue of the heart where adiseased valve has been removed.

A major problem associated with prosthetic valves is tissue valves withgluteraldehyde cross-linked leaflets will calcify and deteriorate overtime.

Another problem is mechanical valves will require anticoagulationagents, such as Coumadin, which can cause side effects in high doses,such as uncontrolled bleeding.

Another problem is the valves do not remodel into normal tissue capableof regeneration and self-repair.

Another problem is many valves must be placed with open heart surgerywhile the patient is on a heart-lung machine.

There is thus a need to provide improved prosthetic tissue valves andmethods for attaching same to cardiovascular structures and/or tissuethat maintain or enhance the structural integrity of the valve whensubjected to cardiac cycle induced stress.

It is therefore an object of the present invention to provide improvedprosthetic tissue valves and methods for implanting same that overcomethe drawbacks and disadvantages associated with conventional prostheticatrioventricular valves.

It is another object of the present invention to provide improvedprosthetic tissue valves and methods for attaching same tocardiovascular structures and/or tissue that maintain or enhance thestructural integrity of the valve when subjected to cardiac cycleinduced stress.

It is another object of the present invention to provide improvedprosthetic tissue valves and methods for attaching same tocardiovascular structures and/or tissue that preserve the structuralintegrity of the cardiovascular structure(s) when attached thereto.

It is another object of the present invention to provide improvedmethods for securely attaching prosthetic tissue valves tocardiovascular structures and/or tissue.

It is another object of the present invention to provide prosthetictissue valves having means for secure, reliable, and consistently highlyeffective attachment to cardiovascular structures and/or tissue.

It is another object of the present invention to provide extracellularmatrix (ECM) prosthetic tissue valves that induce host tissueproliferation, bioremodeling and regeneration of new tissue and tissuestructures with site-specific structural and functional properties.

It is another object of the present invention to provide ECM prosthetictissue valves that induce adaptive regeneration.

It is another object of the present invention to provide ECM prosthetictissue valves that are capable of administering a pharmacological agentto host tissue and, thereby produce a desired biological and/ortherapeutic effect.

SUMMARY OF THE INVENTION

The present invention is directed to prosthetic tissue valves that canbe readily employed to selectively replace diseased or defective heartvalves, and methods for attaching (or anchoring) same to cardiovascularstructures and/or tissue.

In some embodiments of the invention, the prosthetic tissue valvescomprise continuous conical shaped structural members.

In some embodiments of the invention, the prosthetic tissue valvescomprise continuous tubular sheet members.

In some embodiments of the invention, the prosthetic tissue valvescomprise ribbon structures.

In some embodiments of the invention, the ribbon structures comprise aplurality of elongated ribbon members.

In a preferred embodiment of the invention, the edge regions of theribbon members are positioned proximate each other and form a pluralityof fluid flow modulating regions.

In a preferred embodiment, the distal ends of the ribbon members are ina joined relationship, wherein fluid flow through the joined distal endsof the ribbon members is restricted.

In some embodiments of the invention, each ribbon member is also joinedto adjacent ribbon members by an integral coupling member.

In some embodiments of the invention, the proximal end of the prosthetictissue valves includes an annular ring that is designed and configuredto securely engage the prosthetic tissue valves to a valve annulus and,hence, cardiovascular tissue associated therewith.

In some embodiments of the invention, the distal end of the prosthetictissue valves also comprise a structural ring.

According to the invention, the prosthetic tissue valves, annular ringand structural ring can comprise various biocompatible materials.

In some embodiments of the invention, the prosthetic tissue valvesand/or annular ring and/or structural ring comprise an ECM compositioncomprising acellular ECM derived from mammalian tissue.

In a preferred embodiment of the invention, the mammalian tissuecomprises small intestine submucosa (SIS), urinary bladder submucosa(UBS), stomach submucosa (SS), mesothelial tissue, gastrointestinaltissue, tissue surrounding growing bone, placental tissue, omentumtissue, cardiac tissue, kidney tissue, pancreas tissue or lung tissue,and combinations thereof.

In some embodiments of the invention, the ECM composition (and, hence,prosthetic tissue valves and/or annular ring and/or structural ringformed therefrom) further comprises at least one additional biologicallyactive agent or composition, i.e. an agent that induces or modulates aphysiological or biological process, or cellular activity, e.g., inducesproliferation, and/or growth and/or regeneration of tissue.

In some embodiments of the invention, the biologically active agentcomprises a growth factor, including, without limitation, transforminggrowth factor beta (TGF-β), fibroblast growth factor-2 (FGF-2), andvascular epithelial growth factor (VEGF).

In some embodiments of the invention, the biologically active agentcomprises a growth factor, including, without limitation, humanembryonic stem cells, myofibroblasts, mesenchymal stem cells, andhematopoietic stem cells.

In some embodiments of the invention, the biologically active agentcomprises an exosome.

In some embodiments of the invention, the ECM composition (and, hence,prosthetic tissue valves and/or annular ring and/or structural ringformed therefrom) further comprises at least one pharmacological agentor composition (or drug), i.e. an agent or composition that is capableof producing a desired biological effect in vivo, e.g., stimulation orsuppression of apoptosis, stimulation or suppression of an immuneresponse, etc.

Suitable pharmacological agents and compositions include, withoutlimitation, antibiotics, anti-fibrotics, anti-viral agents, analgesics,anti-inflammatories, anti-neoplastics, anti-spasmodics, andanti-coagulants and/or anti-thrombotic agents.

In some embodiments of the invention, the pharmacological agentcomprises a statin, i.e. a HMG-CoA reductase inhibitor, such ascerivastatin.

In some embodiments of the invention, the pharmacological agentcomprises an antibiotic, such as vancomycin and gentamicin.

In some embodiments of the invention, the pharmacological agentcomprises an antimicrobial, such as silver particles and copperparticles.

In some embodiments of the invention, the prosthetic tissue valvesand/or annular ring and/or structural ring comprise a polymericcomposition.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the followingand more particular description of the preferred embodiments of theinvention, as illustrated in the accompanying drawings, and in whichlike referenced characters generally refer to the same parts or elementsthroughout the views, and in which:

FIGS. 1A-1D are schematic illustrations of a human heart;

FIG. 1E is an illustration of a normal mitral valve;

FIG. 1F is an illustration of a prolapsed mitral valve;

FIG. 2A is a perspective view of an embodiment of one prosthetic “ribbonstructure” tissue valve, in accordance with the invention;

FIG. 2B is a perspective view of the tissue valve shown in FIG. 2A in anoperational configuration, in accordance with the invention;

FIG. 2C is a perspective partial sectional view of another embodiment ofthe tissue valve shown in FIG. 2B having a structural ring disposed atthe distal end of the valve, in accordance with the invention;

FIG. 3A is a perspective view of one embodiment of a prosthetic “ribbonstructure” tissue valve having an integral ribbon coupling member, inaccordance with the invention;

FIG. 3B is a perspective view of the tissue valve shown in FIG. 3A in anoperational configuration, in accordance with the invention;

FIG. 3C is a perspective view of another embodiment the tissue valveshown in FIG. 3B having a support ring disposed at the distal end of thevalve, in accordance with the invention;

FIG. 4 is a perspective view of one embodiment of a prosthetic “sheetmember” tissue valve, in accordance with the invention;

FIG. 5 is an illustration of the tissue valve shown in FIG. 2C securedto the mitral valve annulus region, in accordance with the invention;and

FIG. 6 is an illustration of the tissue valve shown in FIG. 2B securedto the mitral valve annulus region, in accordance with the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified apparatus, systems, structures or methods as such may, ofcourse, vary. Thus, although a number of apparatus, systems and methodssimilar or equivalent to those described herein can be used in thepractice of the present invention, the preferred apparatus, systems,structures and methods are described herein.

It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments of the invention only andis not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one having ordinaryskill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein,whether supra or infra, are hereby incorporated by reference in theirentirety.

As used in this specification and the appended claims, the singularforms “a, “an” and “the” include plural referents unless the contentclearly dictates otherwise. Thus, for example, reference to “apharmacological agent” includes two or more such agents and the like.

Further, ranges can be expressed herein as from “about” or“approximately” one particular value, and/or to “about” or“approximately” another particular value. When such a range isexpressed, another embodiment includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about” or“approximately”, it will be understood that the particular value formsanother embodiment. It will be further understood that the endpoints ofeach of the ranges are significant both in relation to the otherendpoint, and independently of the other endpoint.

It is also understood that there are a number of values disclosedherein, and that each value is also herein disclosed as “about” or“approximately” that particular value in addition to the value itself.For example, if the value “10” is disclosed, then “approximately 10” isalso disclosed. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “10” is disclosed then “less than or equal to 10” as well as“greater than or equal to 10” is also disclosed.

DEFINITIONS

The terms “extracellular matrix”, “ECM”, and “ECM material” are usedinterchangeably herein, and mean and include a collagen-rich substancethat is found in between cells in mammalian tissue, and any materialprocessed therefrom, e.g. decellularized ECM.

According to the invention, ECM can be derived from a variety ofmammalian tissue sources and tissue derived therefrom, including,without limitation, small intestine submucosa (SIS), urinary bladdersubmucosa (UBS), stomach submucosa (SS), central nervous system tissue,epithelium of mesodermal origin, i.e. mesothelial tissue, dermal tissue,subcutaneous tissue, gastrointestinal tissue, tissue surrounding growingbone, placental tissue, omentum tissue, cardiac tissue, kidney tissue,pancreas tissue, lung tissue, and combinations thereof. The ECM materialcan also comprise collagen from mammalian sources.

The term “acellular ECM”, as used herein, means and includes ECM thathas a reduced content of cells, i.e. decellularized ECM.

The terms “urinary bladder submucosa (UBS)”, “small intestine submucosa(SIS)” and “stomach submucosa (SS)” also mean and include any UBS and/orSIS and/or SS tissue that includes the tunica mucosa (which includes thetransitional epithelial layer and the tunica propria), submucosal layer,one or more layers of muscularis, and adventitia (a loose connectivetissue layer) associated therewith.

ECM can also be derived from basement membrane of mammalianorgans/tissue, including, without limitation, urinary basement membrane(UBM), liver basement membrane (LBM), and amnion, chorion, allograftpericardium, allograft acellular dermis, amniotic membrane, Wharton'sjelly, and combinations thereof.

Additional sources of mammalian basement membrane include, withoutlimitation, spleen, lymph nodes, salivary glands, prostate, pancreas andother secreting glands.

According to the invention, the ECM can be derived from xenogeneic andallogeneic tissue sources.

ECM can also be derived from other sources, including, withoutlimitation, collagen from plant sources and synthesized extracellularmatrices, i.e. cell cultures.

The term “angiogenesis”, as used herein, means a physiologic processinvolving the growth of new blood vessels from pre-existing bloodvessels.

The term “neovascularization”, as used herein, means and includes theformation of functional vascular networks that can be perfused by bloodor blood components. Neovascularization includes angiogenesis, buddingangiogenesis, intussuceptive angiogenesis, sprouting angiogenesis,therapeutic angiogenesis and vasculogenesis.

The term “adverse inflammatory response”, as used herein, means andincludes a physiological response that is sufficient to induceconstitutive clinically relevant expression of pro-inflammatorycytokines, such as interleukin-1 beta (IL-13) and monocytechemoattractant protein-1 (MCP-1) in vivo.

The term “adverse biological response”, as used herein, means andincludes a physiological response that is sufficient to induce abiological process and/or restrict a phase associated with biologicaltissue healing in vivo, including without limitation, neovascularizationand remodeling of the damaged biological tissue. The term “adversebiological response” thus includes an “adverse inflammatory response”,e.g. development of fibrotic tissue.

The term “biologically active agent”, as used herein, means and includesagent that induces or modulates a physiological or biological process,or cellular activity, e.g., induces proliferation, and/or growth and/orregeneration of tissue.

The term “biologically active agent” thus means and includes a growthfactor, including, without limitation, fibroblast growth factor-2(FGF-2), transforming growth factor beta (TGF-β), and vascularepithelial growth factor (VEGF).

The term “biologically active agent” also means and includes a cell,including, without limitation, human embryonic stem cells,myofibroblasts, mesenchymal stem cells, and hematopoietic stem cells.

The term “biologically active agent” also means and includes an exosomeand/or microsome.

The terms “exosome” and “microsome” as used herein mean and include alipid bilayer structure that contains or encapsulates a biologicallyactive agent and/or pharmacological agent, including, withoutlimitation, a growth factor, e.g. TGF-β, TGF-α, VEGF and insulin-likegrowth factor (IGF-I), a cytokine, e.g. interleukin-8 (IL-8), atranscription factor and micro RNA (miRNA).

The term “biologically active agent” also means and includes agentscommonly referred to as a “protein”, “peptide” and “polypeptide”,including, without limitation, collagen (types I-V), proteoglycans andglycosaminoglycans (GAGs).

The terms “pharmacological agent”, “active agent” and “drug” are usedinterchangeably herein, and mean and include an agent, drug, compound,composition of matter or mixture thereof, including its formulation,which provides some therapeutic, often beneficial, effect. This includesany physiologically or pharmacologically active substance that producesa localized or systemic effect or effects in animals, including warmblooded mammals, humans and primates; avians; domestic household or farmanimals, such as cats, dogs, sheep, goats, cattle, horses and pigs;laboratory animals, such as mice, rats and guinea pigs; fish; reptiles;zoo and wild animals; and the like.

The terms “pharmacological agent”, “active agent” and “drug” thus meanand include, without limitation, antibiotics, anti-arrhythmic agents,anti-viral agents, analgesics, steroidal anti-inflammatories,non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics,modulators of cell-extracellular matrix interactions, proteins,hormones, growth factors, matrix metalloproteinases (MMPs), enzymes andenzyme inhibitors, anticoagulants and/or antithrombotic agents, DNA,RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or proteinsynthesis, polypeptides, oligonucleotides, polynucleotides,nucleoproteins, compounds modulating cell migration, compoundsmodulating proliferation and growth of tissue, and vasodilating agents.

The terms “pharmacological agent”, “active agent” and “drug” thus meanand include, without limitation, vancomycin and gentamicin.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include Class I-Class V antiarrhythmic agents.

The terms “pharmacological agent”, “active agent”, “drug” and “activeagent formulation” further mean and include, without limitation, thefollowing anti-fibrotics: paclitaxel, sirolimus and derivatives thereof,including everolimus.

The terms “pharmacological agent”, “active agent” and “drug” also meanand include a statin, i.e. a HMG-CoA reductase inhibitor, including,without limitation, atorvastatin (Lipitor®), cerivastatin, fluvastatin(Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), mevastatin,pitavastatin (Livalo®, Pitava), pravastatin (Pravachol®, Selektine®,Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®, Lipex®).

Additional biologically active and pharmacological agents are set forthin Co-pending priority U.S. application Ser. No. 15/206,833, which isexpressly incorporated herein in its entirety.

The term “therapeutically effective”, as used herein, means that theamount of the “pharmacological agent” and/or “biologically active agent”and/or “pharmacological composition” and/or “biologically activecomposition” administered is of sufficient quantity to ameliorate one ormore causes, symptoms, or sequelae of a disease or disorder. Suchamelioration only requires a reduction or alteration, not necessarilyelimination, of the cause, symptom, or sequelae of a disease ordisorder.

The terms “patient” and “subject” are used interchangeably herein, andmean and include warm blooded mammals, humans and primates; avians;domestic household or farm animals, such as cats, dogs, sheep, goats,cattle, horses and pigs; laboratory animals, such as mice, rats andguinea pigs; fish; reptiles; zoo and wild animals; and the like.

The term “comprise” and variations of the term, such as “comprising” and“comprises,” means “including, but not limited to” and is not intendedto exclude, for example, other additives, components, integers or steps.

The following disclosure is provided to further explain in an enablingfashion the best modes of performing one or more embodiments of thepresent invention. The disclosure is further offered to enhance anunderstanding and appreciation for the inventive principles andadvantages thereof, rather than to limit in any manner the invention.The invention is defined solely by the appended claims including anyamendments made during the pendency of this application and allequivalents of those claims as issued.

As stated above, the present invention is directed to prosthetic tissuevalves that can be readily employed to selectively replace diseased ordefective valves in the heart, and methods for attaching (or anchoring)same to cardiovascular structures and/or tissue.

In some embodiments of the invention, the prosthetic tissue valvescomprise continuous conical shaped sheet members.

In some embodiments of the invention, the prosthetic tissue valvescomprise ribbon structures.

In some embodiments of the invention, the ribbon structures comprise aplurality of elongated ribbon members.

In a preferred embodiment of the invention, the edge regions of theribbon members are positioned proximate each other and form a pluralityof fluid flow modulating regions.

In a preferred embodiment, the distal ends of the ribbon members are ina joined relationship, wherein fluid flow through the joined distal endsof the ribbon members is restricted.

As indicated above, in some embodiments of the invention, the proximalends of prosthetic tissue valves of the invention comprise an annularring that is designed and configured to securely engage the prosthetictissue valves to a valve annulus (and, hence, cardiovascular tissueassociated therewith).

In some embodiments of the invention, the annular ring comprises atleast one anchoring mechanism that is configured to position theprosthetic tissue valves proximate a valve annulus and maintain contacttherewith for a pre-determined anchor support time period. According tothe invention, the anchoring mechanisms can comprise various forms andmaterials, such as disclosed in U.S. Pat. No. 9,044,319, which isincorporated by reference herein in its entirety.

In some embodiments of the invention, the anchoring mechanisms areconfigured to position ECM prosthetic tissue valves of the inventionproximate a valve annulus and maintain contact therewith for apredetermined temporary anchor support period of time within the processof tissue regeneration.

In some embodiments of the invention, the distal end of the prosthetictissue valves comprises a structural ring.

According to the invention, the prosthetic tissue valves and/or annularring and/or structural ring can comprise various biocompatible materialsand compositions formed therefrom.

In some embodiments of the invention, the prosthetic tissue valvesand/or annular ring and/or structural ring comprise an ECM compositioncomprising acellular ECM derived from a mammalian tissue source.

According to the invention, the ECM can be derived from variousmammalian tissue sources and methods for preparing same, such asdisclosed in U.S. Pat. Nos. 7,550,004, 7,244,444, 6,379,710, 6,358,284,6,206,931, 5,733,337 and 4,902,508 and U.S. application Ser. No.12/707,427; which are incorporated by reference herein in theirentirety.

The mammalian tissue sources include, without limitation, the smallintestine, large intestine, stomach, lung, liver, kidney, pancreas,peritoneum, placenta, heart, bladder, prostate, tissue surroundinggrowing enamel, tissue surrounding growing bone, and any fetal tissuefrom any mammalian organ.

The mammalian tissue can thus comprise, without limitation, smallintestine submucosa (SIS), urinary bladder submucosa (UBS), stomachsubmucosa (SS), central nervous system tissue, epithelium of mesodermalorigin, i.e. mesothelial tissue, dermal tissue, subcutaneous tissue,gastrointestinal tissue, placental tissue, omentum tissue, cardiactissue, kidney tissue, pancreas tissue, lung tissue, and combinationsthereof. The ECM can also comprise collagen from mammalian sources.

In some embodiments, the mammalian tissue source comprises an adolescentmammalian tissue source, e.g. tissue derived from a porcine mammal lessthan 3 years of age.

According to the invention, the ECM can also be derived from the same ordifferent mammalian tissue sources, as disclosed in Co-Pendingapplication Ser. Nos. 13/033,053 and 13/033,102; which are incorporatedby reference herein.

In a preferred embodiment of the invention, the ECM comprises sterilizedand decellularized (or acellular) ECM.

According to the invention, the ECM can be sterilized and decellularizedby various conventional means.

In some embodiments of the invention, the ECM is sterilized anddecellularized via applicant's proprietary process disclosed inCo-Pending U.S. application Ser. No. 13/480,205; which is expresslyincorporated by reference herein in its entirety.

As indicated above, in some embodiments of the invention, the ECMcomposition (and, hence, prosthetic tissue valve and/or annular ringand/or structural ring formed therefrom) further comprises at least oneadditional biologically active agent or composition, i.e. an agent thatinduces or modulates a physiological or biological process, or cellularactivity, e.g., induces proliferation, and/or growth and/or regenerationof tissue.

According to the invention, suitable biologically active agents includeany of the aforementioned biologically active agents, including, withoutlimitation, the aforementioned growth factors, cells and proteins.

Thus, in some embodiments of the invention, the biologically activeagent comprises a growth factor, including, without limitation,transforming growth factor beta (TGF-β), fibroblast growth factor-2(FGF-2), and vascular epithelial growth factor (VEGF).

In some embodiments of the invention, the biologically active agentcomprises an exosome (referred to hereinafter as an “exosome augmentedECM composition”).

As discussed in detail in Applicant's Co-pending U.S. application Ser.No. 15/386,640, exosomes significantly enhance the delivery ofbiologically active agents to cells through two seminalproperties/capabilities.

The first property comprises the capacity of exosomes to shield theencapsulated biologically active agents (via the exosome lipid bilayer)from proteolytic agents, which can, and often will, degrade unshielded(or free) bioactive molecules and render the molecules non-functional inbiological tissue environments.

The second property of exosomes comprises the capacity to directly and,hence, more efficiently deliver biologically active agents to endogenouscells in the biological tissue. As is well known in the art, endogenouscells typically do not comprise the capacity to “directly” interact with“free” biologically active agents, such as growth factors. There must beadditional biological processes initiated by the endogenous cells tointeract directly with biologically active agents, e.g. expression ofreceptor proteins for or corresponding to the biologically activeagents.

As also set forth in Co-pending U.S. application Ser. No. 15/386,640,exosomes facilitate direct interaction by and between endogenous cellsand exosome encapsulated biologically active agents (and, hence, directdelivery of bioactive molecules to endogenous cells), which enhances thebioactivity of the agents.

Thus, it is contemplated that, following placement of a prosthetictissue valve comprising an exosome augmented ECM composition on or in acardiovascular structure (or structures) of a subject, e.g. valveannulus, and, hence, damaged cardiovascular tissue associated therewith,the ECM prosthetic tissue valve will induce a multitude of significantbiological processes in vivo, including significantly enhancedinflammation modulation of the cardiovascular tissue, and significantlyinduced neovascularization, stem cell proliferation, remodeling of thecardiovascular tissue, and regeneration of new tissue and tissuestructures.

By way of example, when an exosome augmented ECM composition comprisingencapsulated IL-8 (and, hence, tissue valve formed therefrom) isdisposed proximate damaged cardiovascular tissue, the exosome augmentedECM composition and, hence, tissue valve formed therefrom modulates thetransition of M1 type “acute inflammatory” macrophages to M2 type “woundhealing” macrophages initiated by the acellular ECM.

By way of further example, when an exosome augmented ECM compositioncomprising encapsulated miRNAs (and, hence, tissue valve formedtherefrom) is disposed proximate damaged cardiovascular tissue, theexosome augmented ECM composition and, hence, tissue valve formedtherefrom induce enhanced stem cell proliferation via the delivery ofexosome encapsulated miRNAs and transcription factors to the damagedcardiovascular tissue, which signals the endogenous stem cells to bindand/or attach to the acellular ECM and proliferate.

According to the invention, the exosomes can be processed and derivedfrom a mammalian fluid composition, including, without limitation,blood, amniotic fluid, lymphatic fluid, interstitial fluid, pleuralfluid, peritoneal fluid, pericardial fluid and cerebrospinal fluid.

The exosomes can also be derived and, hence, processed from in vitro orin vivo cultured cells, including, without limitation, one of theaforementioned cells, e.g., mesenchymal stem cells and hematopoieticstem cells.

The exosomes can also comprise semi-synthetically generated exosomesthat are derived from an exosome producing cell line.

As also indicated above, in some embodiments of the invention, the ECMcomposition (and, hence, prosthetic tissue valve and/or annular ringand/or structural ring formed therefrom) further comprises at least onepharmacological agent or composition (or drug), i.e. an agent orcomposition that is capable of producing a desired biological effect invivo, e.g., stimulation or suppression of apoptosis, stimulation orsuppression of an immune response, etc.

According to the invention, suitable pharmacological agents andcompositions include any of the aforementioned pharmacological agentsand agents set forth in Applicant's Co-pending U.S. application Ser. No.15/206,833.

It is thus contemplated that, in some embodiments of the invention,following placement of a prosthetic tissue valve comprising an ECMcomposition of the invention on or in a cardiovascular structure (orstructures) of a subject, e.g. valve annulus, and, hence, damagedcardiovascular tissue associated therewith, the ECM tissue valve willbecome populated with cells from the subject that will gradually remodelthe ECM into cardiovascular tissue and tissue (and, hence, valve)structures.

It is further contemplated that, following placement of a prosthetictissue valve comprising an ECM composition of the invention on or in acardiovascular structure (or structures) of a subject, and, hence,damaged cardiovascular tissue associated therewith, stem cells willmigrate to the ECM tissue valve from the point(s) at which the valve isattached to the cardiovascular structure or structures.

It is still further contemplated that, during circulation of epithelialand endothelial progenitor cells after placement of an ECM tissue valveon a cardiovascular structure (or structures), the surfaces of an ECMtissue valve will rapidly become lined or covered with epithelial and/orendothelial progenitor cells.

As discussed in detail below, it is still further contemplated that, insome embodiments of the invention, following placement of an ECMprosthetic tissue valve of the invention on or in a cardiovascularstructure (or structures) in a subject and, hence, cardiovascular tissueassociated therewith, the ECM prosthetic tissue valve will induce“modulated healing” of the cardiovascular structure(s) andcardiovascular tissue associated therewith.

It is still further contemplated that the points at which an ECM tissuevalve is attached to a cardiovascular structure (or structures) in asubject will serve as points of constraint that direct the remodeling ofthe ECM into cardiovascular tissue and valve structures that areidentical or substantially identical to properly functioning nativecardiovascular tissue and valve structures.

As indicated above, in some embodiments of the invention, the prosthetictissue valves comprise a polymeric composition comprising abiodegradable polymeric material. According to the invention, suitablepolymeric materials, include, without limitation, polyurethane urea,porous polyurethane urea (Artelon®), polypropylene, poly(ε-caprolactone)(PCL), poly(glycerol sebacate) (PGS) and polyethylene terephthalate(Dacron®).

According to the invention, in some embodiments of the invention, theannular ring and/or structural ring similarly comprise a polymericcomposition comprising a biodegradable polymeric material. According tothe invention, suitable biodegradable polymeric materials comprise,without limitation, polycaprolactone (PCL), porous polyurethane urea(Artelon®), polyglycolide (PGA), polylactide (PLA), poly(s-caprolactone)(PCL), poly dioxanone (a polyether-ester), poly lactide-co-glycolide,polyamide esters, polyalkalene esters, polyvinyl esters, polyvinylalcohol, and polyanhydrides.

According to the invention, the polymeric composition can furthercomprise a natural polymer, including, without limitation,polysaccharides (e.g. starch and cellulose), proteins (e.g., gelatin,casein, silk, wool, etc.), and polyesters (e.g., polyhydroxyalkanoates).

The polymeric composition can also comprise a hydrogel composition,including, without limitation, polyurethane, poly(ethylene glycol),poly(propylene glycol), poly(vinylpyrrolidone), xanthan, methylcellulose, carboxymethyl cellulose, alginate, hyaluronan, poly(acrylicacid), polyvinyl alcohol, acrylic acid, hydroxypropyl methyl cellulose,methacrylic acid, αβ-glycerophosphate, η-carrageenan,2-acrylamido-2-methylpropanesulfonic acid, and β-hairpin peptide.

In some embodiments of the invention, the polymeric compositioncomprises poly(urethane urea); preferably, Artelon® distributed byArtimplant AB in Goteborg, Sweden.

In some embodiments, the polymeric composition comprises poly(glycerolsebacate) (PGS).

According to the invention, the polymeric composition can furthercomprise a non-biodegradable polymer, including, without limitation,polytetrafluoro ethylene (Teflon®) and polyethylene terephthalate(Dacron®).

In some embodiments of the invention, annular ring and/or structuralring comprise a biocompatible metal. According to the invention,suitable metals comprise, without limitation, Nitinol®, stainless steeland magnesium.

As indicated above, in some embodiments of the invention, it iscontemplated that, following placement of an ECM prosthetic tissue valveof the invention on or in a cardiovascular structure (or structures) ina subject and, hence, cardiovascular tissue associated therewith, theECM prosthetic tissue valve will induce “modulated healing” of thecardiovascular structure(s) and cardiovascular tissue associatedtherewith.

The term “modulated healing”, as used herein, and variants of thislanguage generally refer to the modulation (e.g., alteration, delay,retardation, reduction, etc.) of a process involving different cascadesor sequences of naturally occurring tissue repair in response tolocalized tissue damage or injury, substantially reducing theirinflammatory effect. Modulated healing, as used herein, includes manydifferent biologic processes, including epithelial growth, fibrindeposition, platelet activation and attachment, inhibition,proliferation and/or differentiation, connective fibrous tissueproduction and function, angiogenesis, and several stages of acuteand/or chronic inflammation, and their interplay with each other.

For example, in some embodiments of the invention, the ECM prosthetictissue valves of the invention are specifically formulated (or designed)to alter, delay, retard, reduce, and/or detain one or more of the phasesassociated with healing of damaged tissue, including, but not limitedto, the inflammatory phase (e.g., platelet or fibrin deposition), andthe proliferative phase when in contact with biological tissue.

In some embodiments, “modulated healing” means and includes the abilityof an ECM prosthetic tissue valve of the invention to restrict theexpression of inflammatory components. By way of example, according tothe invention, when a prosthetic tissue valve (and/or annular ringand/or structural ring) of the invention comprises a statin augmentedECM composition, i.e. a composition comprising ECM and a statin, and theECM prosthetic tissue valve is positioned proximate damaged biologicaltissue, e.g., attached to a valve annulus, the ECM prosthetic tissuevalve restricts expression of monocyte chemoattractant protein-1 (MCP-1)and chemokine (C—C) motif ligand 2 (CCR2).

In some embodiments of the invention, “modulated healing” means andincludes the ability of an ECM prosthetic tissue valve of the inventionto alter a substantial inflammatory phase (e.g., platelet or fibrindeposition) at the beginning of the tissue healing process. As usedherein, the phrase “alter a substantial inflammatory phase” refers tothe ability of a prosthetic tissue valve of the invention tosubstantially reduce the inflammatory response at a damaged tissue site,e.g. valve annulus, when in contact with tissue at the site.

In such an instance, a minor amount of inflammation may ensue inresponse to tissue injury, but this level of inflammation response,e.g., platelet and/or fibrin deposition, is substantially reduced whencompared to inflammation that takes place in the absence of an ECMprosthetic tissue valve of the invention.

The term “modulated healing” also refers to the ability of an ECMprosthetic tissue valve of the invention to induce host tissueproliferation, bioremodeling, including neovascularization, e.g.,vasculogenesis, angiogenesis, and intussusception, and regeneration ofnew tissue and tissue structures with site-specific structural andfunctional properties, when disposed proximate damaged tissue, e.g.valve annulus.

Thus, in some embodiments of the invention, the term “modulated healing”means and includes the ability of an ECM prosthetic tissue valve of theinvention to modulate inflammation and induce host tissue proliferationand remodeling, and regeneration of new tissue when disposed proximatedamaged tissue.

It is further contemplated that, during a cardiac cycle after placementof an ECM prosthetic tissue valve on a valve structure or structures,wherein the ECM prosthetic tissue valve is subjected to physicalstimuli, adaptive regeneration of the prosthetic tissue valve is alsoinduced.

By the term “adaptive regeneration,” it is meant to mean the process ofinducing modulated healing of damaged tissue concomitantly withstress-induced hypertrophy of an ECM prosthetic tissue valve of theinvention, wherein the ECM prosthetic tissue valve adaptively remodelsand forms functioning valve structures that are substantially identicalto native valve structures.

As indicated above, it is further contemplated that the points at whichan ECM prosthetic tissue valve is attached to a cardiovascular structure(or structures) in a subject will serve as points of constraint thatdirect the remodeling of the ECM into cardiovascular tissue and valvestructures that are substantially identical to properly functioningnative cardiovascular tissue and valve structures.

Referring now to FIGS. 2A and 2B, there is shown one embodiment of aprosthetic “ribbon structure” tissue valve of the invention, where FIG.2A illustrates the prosthetic tissue valve, denoted 10 a, in apre-deployment configuration and FIG. 2B illustrates the prosthetictissue valve 10 a in a deployed operational configuration.

As illustrated in FIGS. 2A and 2B, in a preferred embodiment of theinvention, the prosthetic tissue valve 10 a comprises a base member 50comprising a proximal valve annulus engagement end 52 having acircumferential ribbon connection region 58, and a distal end 54. Thebase member 50 further comprises a plurality of ribbon members orribbons 56 that are connected to and extend from the ribbon connectionregion 58.

As further illustrated in FIGS. 2A and 2B, each of the plurality ofribbons 56 comprise proximal and distal ends 56 a, 56 b, and first andsecond edge regions 53 a, 53 b that extend from the circumferentialribbon connection region 58 to the distal ends 56 b of each of theribbons 56 and, hence, distal end 54 of the base member 50.

In a preferred embodiment, the base member 50 similarly comprises an ECMcomposition comprising acellular ECM derived from one of theaforementioned mammalian tissue sources.

As illustrated in FIG. 2B, in some embodiments, the ribbons 56 of theformed valve 10 a taper to a substantially coincident point 55, whereinthe base member 50 has a substantially conical shape.

In a preferred embodiment, the distal ends 56 b of the ribbons 56 are ina joined relationship, wherein fluid flow through the joined distal ends56 b of the ribbons 56 is restricted.

As further illustrated in FIG. 2B, the proximal ends 56 a of ribbons 56are positioned circumferentially about the circumferential ribbonconnection region 58 of the base member 50, wherein the first edgeregions 53 a and the second edge regions 53 b of the ribbons 56 arepositioned adjacent each other and form a plurality of fluid flowmodulating regions 59.

In a preferred embodiment of the invention, the base member 50 isconfigured to expand during positive fluid flow through the base member50, as shown in phantom and denoted 50′, and contract during negativefluid flow through the base member 50, e.g. regurgitating blood flow.

In a preferred embodiment, the fluid flow modulating regions 59 areconfigured to open during expansion of the base member 50′ (as shown inphantom and denoted 59′), i.e. the first and second edge regions 53 a,53 b separate, as shown in phantom and denoted 53 a′, 53 b′, wherein thepositive fluid flow is allowed to be transmitted through the fluid flowmodulating regions 59′, and close during the contraction of the basemember 50, wherein the negative fluid flow through base member 50 isrestricted, more preferably, abated.

According to the invention, the base member 50 can comprise any numberof ribbons 56. In some embodiments of the invention, the base member 50has four (4) equally spaced ribbons 56.

According to the invention, the proximal end of the prosthetic tissuevalves of the invention preferably comprise a circumference, i.e.operative valve circumference, in the range of approximately 20 mm to220 mm.

According to the invention, the prosthetic tissue valves of theinvention can also comprise any length. In some embodiments of theinvention, the prosthetic tissue valves 10 f have a length in the rangeof approximately 10 mm to 100 mm.

Referring now to FIG. 2C, there is shown another embodiment of theprosthetic tissue valve 10 a that is shown in FIGS. 2A and 2B. Asillustrated in FIG. 2C, the prosthetic tissue valve, now denoted 10 b,includes a support ring 40 that is disposed on the distal end 54 of thevalve 10 b.

According to the invention, the structural ring 40 is preferably sizedand configured to receive ribbons 56 therein in close proximity to eachother, as shown in FIG. 2C.

Referring now to FIGS. 3A and 3B there are shown further embodiments ofprosthetic “ribbon structure” tissue valves (denoted “10 c” and “10 d”).As illustrated in FIGS. 3A and 3B, the tissue valves 10 c, 10 d alsocomprise a base member 50 comprising a proximal valve annulus engagementend 52 having a circumferential ribbon connection region 58, and adistal end 54. The base member 50 further comprises a plurality ofribbon members or ribbons 56 that are connected to and extend from theribbon connection region 58.

As further illustrated in FIGS. 3A and 3B, in a preferred embodiment,the tissue valves 10 c, 10 d further comprise at least one constrainingband or coupling member (denoted “70 a” in FIG. 3A and “70 b” in FIG.3B). According to the invention, the coupling member is sized andconfigured to couple (or join) a ribbon 56 to adjacent ribbons, i.e.couple a first edge region 53 a of a first ribbon 56 to the second edgeregion 53 b of a second ribbon 56, at a predetermined region.

More preferably, the tissue valves 10 c, 10 d comprise a plurality ofcoupling members that are sized and configured to couple (or join) eachribbon 56 to adjacent ribbons at a predetermined region.

According to the invention, the coupling members 70 a, 70 b can bedisposed at any region between the proximal and distal ends 56 a, 56 bof the ribbons 56.

The coupling members 70 a, 70 b can also comprise any length.

According to the invention, the coupling members 70 a, 70 b can compriseseparate or integral members. The coupling members 70 a, 70 b can alsocomprise a combination of separate and integral members.

According to the invention, the separate coupling members (not shown)can be attached to the ribbons via conventional means, e.g., suturing oran adhesive composition.

According to the invention, suitable adhesive compositions include,without limitation, poly(glycerol sebacate) (PGS), poly(glycerolsebacate) acrylate (PGSA) and collagen-based compositions.

According to the invention, the adhesive compositions can be crosslinkedand/or cured via the combination of a photoinitiator and radiation.

In a preferred embodiment, the coupling members 70 a, 70 b compriseintegral members, such as illustrated in FIGS. 3A and 3B, wherein acontinuous prosthetic valve structure is provided.

In some embodiments of the invention, not shown, the coupling members 70a, 70 b are sized and configured to intersect or cross each other.

Referring now to FIG. 3C, there is shown another embodiment of theprosthetic tissue valve 10 d that is shown in FIG. 3B. As illustrated inFIG. 3C, the prosthetic tissue valve, now denoted 10 e, similarlycomprises a structural ring 40 that is disposed on the distal end 54 ofthe valve 10 e.

In some embodiments of the invention, the prosthetic tissue valves 10 dand 10 e further comprise a supplemental support structure, such asdescribed in Applicant's Co-pending U.S. application Ser. No.15/206,871.

Referring now to FIG. 4, there is shown another embodiment of aprosthetic tissue valve of the invention (denoted “10 f”). Asillustrated in FIG. 4, the tissue valve 10 f comprises a continuousconical shaped sheet member 30.

In a preferred embodiment, the sheet member 30 similarly comprises anECM composition comprising acellular ECM derived from one of theaforementioned mammalian tissue sources, including, without limitation,small intestine submucosa (SIS), urinary bladder submucosa (UBS),mesothelial tissue, placental tissue and cardiac tissue.

As illustrated in FIG. 4, the tissue valve 10 f further comprisesproximal and distal ends 32, 34, and a plurality of open regions orinterstices 36 a-36 d that are preferably disposed linearly over aportion of the length of the sheet member 30.

As discussed in detail in Co-pending U.S. application Ser. No.15/206,833, the sheet member 30 is preferably configured to expandduring positive fluid flow through the sheet member 30, as shown inphantom and denoted 30′, and contract during negative fluid flow throughthe sheet member 30, e.g. regurgitating blood flow.

The interstices 36 a-36 d are also preferably configured to open duringthe noted expansion of the conical shaped member 30′ (denoted 36 a′, 36b′, 36 c′ and 36 d′), wherein the positive fluid flow is allowed to betransmitted through the interstices 36 a′, 36 b′, 36 c′, 36 d′, andclose during the noted contraction of the sheet member 30, wherein thenegative fluid flow through said member 30 is restricted, morepreferably, abated.

Referring now to FIGS. 5 and 6, there are shown tissue valve 10 b and 10a, respectively, disposed in mitral valve regions of a subject.Placement of the valves 10 b and 10 a in the mitral valve regions isdescribed in detail in Applicant's Co-pending U.S. application Ser. No.15/206,833.

As indicated above, it is contemplated that, when the prosthetic tissuevalves of the invention comprise an ECM composition comprising acellularECM (i.e. ECM prosthetic tissue valves), upon placement of the ECMprosthetic tissue valves to a valve structure, e.g., valve annulus 105,modulated healing of the valve structure and connecting cardiovascularstructure tissue will be effectuated.

It is further contemplated that, following placement of the ECMprosthetic tissue valve of the invention on or in a cardiovascularstructure (or structures) of a subject, the ECM prosthetic tissue valveswill become populated with cells from the subject that will graduallyremodel the ECM into cardiovascular tissue and tissue (and, hence,valve) structures.

It is further contemplated that, following placement of the ECMprosthetic tissue valves of the invention on a cardiovascular structure(or structures) in a subject, stem cells will migrate to the ECMprosthetic tissue valves from the point(s) at which the valves areattached to the cardiovascular structure, e.g., valve annulus, orstructures, e.g., valve annulus and heart wall.

It is still further contemplated that the points at which the ECMprosthetic tissue valves of the invention are attached to acardiovascular structure (or structures) in a subject will serve aspoints of constraint that direct the remodeling of the ECM intocardiovascular tissue and valve structures that are identical orsubstantially identical to properly functioning native cardiovasculartissue and valve structures.

Without departing from the spirit and scope of this invention, one ofordinary skill can make various changes and modifications to theinvention to adapt it to various usages and conditions. As such, thesechanges and modifications are properly, equitably, and intended to be,within the full range of equivalence of the following claims.

What is claimed is:
 1. A prosthetic valve for modulating fluid flowthrough a cardiovascular structure during cardiac cycles of a heart,said fluid flow exhibiting a plurality of positive and negative flowpressures during said cardiac cycles, said prosthetic valve comprising:a base valve structure comprising an extracellular matrix (ECM)composition, said ECM composition comprising acellular ECM from amammalian tissue source, said base valve structure further comprising anopen proximal valve annulus engagement end, a distal end, and aplurality of elongated ribbon members, said proximal valve annulusengagement end being configured to engage a valve annulus region of saidcardiovascular structure, said proximal valve annulus engagement end,when engaged to said valve annulus region of said cardiovascularstructure, being further configured and adapted to receive said fluidflow therein and direct said fluid flow into said base valve structure,said proximal valve annulus engagement end comprising a circumferentialribbon member connection region, each of said plurality of elongatedribbon members comprising a proximal end, a distal end, and a mid-ribbonmember region disposed between said proximal and distal ends of saidplurality of elongated ribbon members, said proximal ends of saidplurality of elongated ribbon members being connected to saidcircumferential ribbon member connection region, whereby said pluralityof elongated ribbon members project from said proximal valve annulusengagement end to said base valve structure distal end, each of saidplurality of elongated ribbon members further comprising a first edgeregion that extends from said proximal end of each of said plurality ofelongated ribbon members to said distal end of each of said plurality ofelongated ribbon members and a second edge region that extends from saidproximal end of each of said plurality of elongated ribbon members tosaid distal end of each of said plurality of elongated ribbon members,said plurality of elongated ribbon members being positionedcircumferentially about said circumferential ribbon member connectionregion, wherein said first edge regions of said plurality of elongatedribbon members are positioned proximate said second edge regions of saidplurality of elongated ribbon members and a plurality of fluid flowmodulating regions is formed between adjacent elongated ribbon membersof said plurality of elongated ribbon members, said distal ends of saidplurality of elongated ribbon members being engaged to each other in ajoined relationship at said base valve structure distal end, whereinsaid fluid flow through said distal end of said base valve structure isrestricted during said fluid flow into said base valve structure whilesaid fluid flow is allowed to be transmitted through at least one ofsaid fluid flow modulating regions when said at least one of said fluidflow modulating regions is in an open position, said base valvestructure further comprising at least one coupling member that connectssaid first edge region of a first elongated ribbon member of saidplurality of elongated ribbon members to said second edge region of anadjacent second elongated ribbon member of said plurality of elongatedribbon members, said at least one coupling member being connected tosaid mid-ribbon member regions of said first elongated ribbon member andsaid adjacent second elongated ribbon member of said plurality ofelongated ribbon members, whereby, said first elongated ribbon memberand said adjacent second elongated ribbon member of said plurality ofelongated ribbon members are coupled together, said base valvestructure, when engaged to said valve annulus region of saidcardiovascular structure and receives said fluid flow therein, beingconfigured to transition from a pre-expanded position to an expandedposition when said fluid flow exhibits a first positive flow pressure ofsaid plurality of positive flow pressures, each of said plurality offluid flow modulating regions being configured to transition from adosed position when said base valve structure is in said pre-expandedposition, wherein each of said plurality of fluid flow modulatingregions and said distal end of said base valve structure restricts saidfluid flow through said base valve structure, to said open position whensaid base valve structure transitions to said expanded position, whereineach of said plurality of fluid flow modulating regions allows saidfluid flow to be transmitted through said plurality of fluid flowmodulating regions while said distal end of said base valve structurerestricts said fluid flow through said distal end of said base valvestructure, said base valve structure being further adapted to remodelinto cardiovascular tissue and native valve structures and induceremodeling of damaged cardiovascular tissue and regeneration of newcardiovascular tissue when said proximal valve annulus engagement end ofsaid base valve structure is engaged to said valve annulus region ofsaid cardiovascular structure.
 2. The prosthetic valve of claim 1,wherein said mammalian tissue source is selected from the groupconsisting of small intestine submucosa (SIS), urinary bladder submucosa(UBS), urinary basement membrane (UBM), liver basement membrane (LBM),stomach submucosa (SS), mesothelial tissue, placental tissue, omentumtissue, heart tissue and lung tissue.
 3. The prosthetic valve of claim1, wherein said ECM composition further comprises at least oneexogenously added biologically active agent.
 4. The prosthetic valve ofclaim 3, wherein said biologically active agent comprises a cellselected from the group consisting of a human embryonic stem cell, fetalcardiomyocyte, myofibroblast, and mesenchymal stem cell.
 5. Theprosthetic valve of claim 3, wherein said biologically active agentcomprises a growth factor selected from the group consisting oftransforming growth factor-beta (TGF-β), fibroblast growth factor-2(FGF-2), and vascular epithelial growth factor (VEGF).